Research: The research goal of our laboratory is to understand the molecular mechanism of Tumor Necrosis Factor (TNF) signaling and the regulation of apoptosis. TNF Signal transduction. TNF is a proinflammatory cytokine that plays a critical role in diverse cellular events. Upon TNF treatment, cells could undergo proliferation, differentiation and apoptosis. In previous a study, we found that the activation of transcription factors NF-kB and AP-1 as well as the induction of apoptosis are mediated by three distinct pathways in response to TNF. While the adaptor molecule FADD mediates apoptosis, the death domain kinase RIP and the TNF receptor associated factor TRAF2 are essential for NF-kB and AP-1 activation. Last year we found that TRAF2 recruited IKK to TNF-R1 complex in response to TNF treatment. Although RIP is not required for IKK recruitment, it is essential for IKK activation. Since the kinase that directly activates IKK is still unknown, we try to identify this kinase with several different approaches. Using MEKK3-/- fibroblasts, we recently reported that MEKK3 plays a critical role in TNF-induced IKK activation. Regulation of apoptosis. Apoptosis (Programmed Cell Death) is a common phenomenon during development and used to eliminate harmful or unwanted cells from the organism. Apoptosis is the crucial process for organisms to keep their cellular homeostasis. Deregulation of apoptosis is involved in many diseases, for instance, inefficient apoptosis has been found in many different cancers. Since all cells have the genetic machinery required to commit suicide, the ability to selectively regulate this process has profound implications for treating disease. Because more and more evidence indicates that irregular cell growth often leads to apoptosis, we believe that in addition to the promoting growth signals, inactivation of apoptosis is essential for normal cells to become tumor cells. This can be achieved by either increasing a signal that actively blocks apoptosis or generating a defective mutation in the cell death machinery. Identification of these apoptosis-inactivating targets in different cancers will greatly enrich our knowledge about tumorigenesis and help to develop new cancer therapies. One of our research interests is to identify the genes that protect cancer cells from apoptosis and, upon understanding the mechanisms of their actions, to develop new cancer therapies. To do so, we use tumor necrosis factor (TNF)-mediated apoptosis as a model system. It is known that the activation of NF-kB protects cells from apoptosis induced by TNF and many chemothapeutic agents. While we continue to study the regulation of TNF signal transduction, We also like to understand the mechanism of the transcription factor NF-kB mediated anti-apoptotic effect. Using several different approaches including microarray, we have identified some candidate genes which may protect cells from apoptosis. Currently we are further testing their anti-apptotic effect. Because NF-kB activation protects cells against apoptosis and also is essential for the development of several types of cancer, the identification of the anti-apoptotic genes activated by NF-kB will provide new targets for developing new cancer therapies. Inhibition of the functions of these anti-apoptotic genes may result in apoptosis of cancer cells and lead to cure of the disease.